ORIGINS and DEVELOPMENT of SCHIZOPHRENIA ADVANCES (N EXPERIMENTAL PSYCHOPATHOLOGY eaited by MARK F. LENZENWEGER ROBERT H. DWORKIN 998A Two-Hit Working Model of the Etiology of Schizophrenia Sarnoff A. Mednick, Jennifer B. Watson, ‘Matti Huttunen, Tyrone D. Cannon, Heikki Katila, Ricardo Machon, Birgitte Mednick, Meggin Hollister, Josef Parnas, Fini Schulsinger, Nina Sajaniemi, Peter Voldsgaard, Reijo Pyhala, Dan Gutkind, and Xueyi Wang Wiizeriss nest meat! ain he bs of sein phienia This model was shaped bythe findings of four major longiinal projec: the Copenhagen High-Risk Projet te etal Viel Infection Proje, she Denigh Birth Cohort, end the Copenagsn and Helsiaki Habituation Projects Fist an ouline ofthe two-hit models preented followed by a dscasson of Ging fom the four projets, ‘The chapter ende with bypother and diecusion of the tina a sociated with an earthquake ia Chins The working model of the fist hit inciaes the flowing: 1 The fist hit stems fom a gente Hability for schizophrenia Thie onetieHabilty exosits of 2 preprogrammed disoption of fea ‘neural development during a psiod af gestation eral for sho prc 2 This dsuption can be partly mimicked by adventitious terato- geri factors tht cole with the critical ural development pe "od for schizophrenia. An example ofan adventitious teatogen i ‘tera infenes infection in the 2nd trimester Ss. Alhough ici clear that a teratogen may be serious enough kl heets in many te the ef of the gna drpton may be move serious and exensve than the eff ofan advensisous ratogen 4. The iat hit geetc or tertoge) creates 3 vulerbiity fr shiz Peni decompensation. 1 the individuals perinatal and eidhood fexpticncs are ee of severe sues he or she will exhibit adult be- vie ha approximate the Digg nd Stati! Maa of Mer fal Dione (ath od. [DSMIV]; Amurcan Pechatsc Asocaon [APA], 1954) dignos of ahinotypal or paranoid personaly durder The working mods! of the second hit includes the following: 5 The second hit can tae the form of dlery complications (DCH) ‘or nonoptunal ely child rening "The nate of the eevond hit helps dermine the poychopahologcl course of fness 6 For those mate vlourble by the Bs it, DCs may damage per ‘eisiuar bean rogions (atcited with the autonomic nervous fystamte etary functioning), which may contribute to severe ‘educions in emotional rsponding and expresion (Cannon et, 1988, Cannon, Mednick, Parnas, 19902) This DC-related damage may increase risk for schizophrenia with predomioandy negative ‘mptoms 17, ‘Thon rade vnerable by the feet it wh dd nt sir sree DCs may eaperience decompanation if they encounte severe sremes during ext childhood Fr sich individ who have responsive ‘sstonemic neous sts the stoss my cause them o deco ‘enste with predominantly postive symptom schizophrenia, 1 Those with DCs that lead to perivenicolar damage wll have i ceased risk for predominantly negative symptoms regardless af the Dresenct or absence ofchildood arencrs PROJECT 1 THE 1962 COPENHAGEN HIGH-RISK PROJECT “The 1962 Copenhagen High-Risk Project was developed in 1950 in response tothe difcicin examining the elogy of schizophve Dr corapering opti’ scizopheens patients with normal cotels 2% ‘The high-k projec reaarch design provides © method for invest sting premorbid rk factors that clate to the development of china Phrenia and other psychotic nesses In highrisk design, the off spring of the schizophrenic parents re thn fllowed longitudinally with stesments ofthe atk children cootining into adulthood The purpose ofthe project wat to examine children before they sufeed the consequences of schizophrenia and to arempt to identify premorbid factors that distinguish future schizpbrenia patients These premorbid Astingishing characterises may contribute t the development of 2 ‘beter understanding of evioloay Research Design and Methods The original 1962 Copenhagen High-Risk Project examined 207 eit ren with scizopheenle modbers and 104 contol patiipants We st amined them exesvely wien they were (om average) 15 1 years of age The purpose of the project wat to examine children before they sired the consequences of schizophrenia and t attempt to ie premorbid factors that diingish ftir schizophrenia patents These remorbid distinguishing characteristics may contbute tothe devel. opment of 2 beter understanding of etiology Diagnostic Methods Paychinric functioning was appeased in 1972-1974 when the patients were mean age of 25 years and agin a 19861989 whea the patients were a mesa apt of 39 years The diagnostic procedure in 1972-1974 Included two structured interviews, cach of which allowed the inter et arive ata dagnosis the Present State Examination (PSE; Wing, Cooper & Saroras, 1974) and the Catrent and Past Psycho: pathology Scales (Endicot & Spiver, 1972) The prchopathologicl ate fom this asessment were later converted into. DSMCUILR (3rd 4 roxy APA, 1987) diagnoses (Parnas eta, 1993) The procedure ia 1986-1989 included an administration of the Schedule foe fective Disorders and Schizophrenia Lifetime Vession (Spier & Endicot, 1977, the PSE, the PSE lfeime ratings of psychotic symptoms, the PSE syndrome cheellit for curcent and eine payhopatology the »Scale forthe Awessment of Positive Symptoms (Andreasen, 19636), the Scale for the Assesment of Negative Symptoms (Andresen, 1983), and the Personality Disorder Examination (Loranger, Ssman, Oldman, & Russakoff, 1988) Exciing those who died or engrted, ‘more than 90% of the sample orginally Seen in 1962 wae asin in this manner In addon, the ene sample was screened in the ne tional pcs register Information, tus clei, was wzed to determine Ais {and I DDSM-II-R diagnoses for sac nada at sch asesinent An inde endent analysis ofthe interview data yee igh ate of epeement Wide the exginal diagnoses (ee = 90-95) A ltime DSMCITR di agnosis was determined (Parma eta, 193) [A total of 126 high-tdeand 77 lowers patients underwent compu ‘aed tomography (Ct) sanaing a prt of the 1986-1989 svewment Patients sanned were representative afte original sample with respect to ag, gender, risk stata, ifetime payhiaric dings and isory of perinatal complications Scant were performed on a CT scanner (52 ‘maton DRG, Siemens, si, NJ) at Hvidowe Hospital in Copenhagen (Denna) An avecage of 13 ses ws taken pall o the suprior titomeial line cach with a shickaess af § mm and no oveap Images ‘wpre processed on 2256 %, 236 matic ‘A cemioutomstad computer algorithm was uscd to obtain vla- metric ares and linear measurements ofthe eb spinal i (CSE) spaces in dhe region of the ventricles and corti! sul (both overall ‘ad for the frontal interhemispheric fare and the right and ey inn Sssues separately), which were then expaned a percentage of (olor hemispheric) beat value, ste, and width, respectively All rearasements were then stundardzed tothe same metic (ie, M5, SD= 1). ‘Most births in Denmark are atended by midwives who complete & standardized form concerning the course ofthe delivery as well the ‘pre-and postnatal conditions of the mothe and newborn, The infor x mation avilable in the protocol is considered by Danish obsttcans to be scurate but not neesariy easing ome complications may Ihave occurred bat were net reported (especially milder complications) Protocol were obtained for 155 high ck paint In our working mods, DCs represent ane type of second hit. The complications iacaded inthe DC index ae as fellows (each compl ‘tion cots one point the total snr) abnoraal fetal polo, premature rupture of membranes, vagina explorations stimulants phyla pelvic contractions during delivery, bkeding during delivery averine ine, afi hep {eg ora Caesar section), ow t0 low-normal birth weight, and prolonged labor Previous work has in cated that low to loe-nottal birth weight and prolnged labor tee sre asocnted with = heightened suk of perinatal hypesa (seduction of enygen supply to the Sess during the birth prose) and intaven tricular hemorhaging (Brann, 1985), bo of which may led to ne cross of cella and enlargement ofthe vesicular sstrn Foe thi te $00, bith weights in the boaom quartile ofthe distribution (las than $3100 g) and labor imer in the upper quarse of the dtbution (Grete than 17h) were each scored as one complication; 46 patients had 0 complications, 5 had one complication, and 65 had two or more complistione High-Risk Project, Hypothesis 1 For the High-Risk Project, our fst hypothesis stipulates that genetic sik for schizophrenia will inceate valerabilty 10 environmental trauma (econd hit) We propose that a lee of genetic risk increase, DCs will be asoiste wth multiplicative increase in anomalies of| the bait Background A fetus with 2nd-timester devopmentl handicap (ft it) then ‘ea bith I is possible thar the resultant nearal anomalies, vascular bin developmental anomalies, oF both produc a special vlnerabity| ofthe high-vise ews to DCs. This may make the bigh-ik fetuses Pcally wlnerble 0 the ates of «difieuk birth and may crease afor bldg in the venrsls, anos lack of onype), and damage to privet tase "The resus of two plo ste (Canon & Mednick, 1989; Cannon tal, 1983), bond on the 15 schizophrenia point identified in 1972, Support the hypotees derived fom the working moda In 1986198, ‘wr sommpeted a diagnostic zene of ee 1982 high-risk sample a ‘Secrped 31 schinoprenia patients in the high-k group Cannon snd Mednick were she to test the working medel more decisively wit {is larger group of schiophsenia patents The scond atic (Canon ‘2, 1993) following this atest seesment examines he hypothesized {atersction beoween fenetic predisposing and DCs These researchers wed cohort analrtic study of 60,72, and 25 individuals with zero, ‘one or Owe parent especialy, whe were feted wth schizophreie- ‘pectrum eordre They were examined in 1986-1989 with psychiase interviows and CT seas Resales "here were sgpiicant ea inceases in OSF—bran ratios in the seal repions ofthe cerebral cortex ae «Senctin of eel of genet ik (se Fipuce 1) lnivdual with no afected parents evidenced greater cor til sual enlargement chan did individuals wih one afeted parent Tin tarn, advo with oe affected parent evidenad greater coetal real colagement than dit indsiduls with no affected parents. In ‘ion, gente disk for echizopenia and DCs were found ta atrace in the peaickn ofthe subortical (Je, wesc) CSEbaineatio “The effect of DCe was greter emg those with we schizophrenic or chisophrenia-specturn) parts compared with those with one af fected parent and greater among those wih one aed parent eam pared with those of normal parents These effects were signiiant far Contoling forthe cscs of ape gender, substance abuse, and history of ong brn eyndeomes and head injaree Discusion We interpre he cortical anomalies a resulting fom the genetic ist hut (dsroptons in fel neural development) and the subcortical ve ‘cular abrormates having resulted from a send bit, DCs 2 Foal io} ce = al 2 Gene ik soph ad rege C-tea ‘pind Sd LA Tow a R= gh te SR hh hh oe High-Risk Project, Hypothesis 2 ‘Thee ndings leds to hypothesize that schinphrenia patients end individual with genetically rated conditions (schizotypal) would Stare te cortical anomalies (lative slealenargement) whereas only schizophrenia patients (not schizotypal patents) would evidence the ‘estar enlargement Background “There is consistent body of evidence ndising a genetic rasonship between schizophrenia and schizotypal personality disorder (SPD) In view of this, one would expect to Gnd simlar dstbusions of (ge netcaly rte) cortical bean abnormalities among individuals with SPD and schizophrenia, We predic that among offing of schizo ‘Phrenic parent, those who develop schizophrenia or SPD will eve ence an equivalent deice of cortical sulcal elargement and thet both groups will evidence grenter cortical sual enlargement than bigh-rsk indvidsale with noaspecrum psychiatric dkordere and zo dvorders and low-risk indvideale with and without poehitrc 3sisorders. tn ation, we poediced dat high-tic indviduale with ‘chizophcenia wil evidence « pester degree of vesticular ear seat than high-sk individuals with SPD, nonspectrum payin ‘orders and no disorders snd low-rik individ with an those without psychiatric disorders Metiods ‘We used the cohort analytic study ofthe following six groups: high sis patios: (1) 17 with eehizophenia, (2) St with SPD, (3) 38 th nonspecram payhlatsie uerder and (4) 45 with no pach ‘ede, lowes patients: (3) 31 with nonspectram payhitic dade ‘ofall pet and (6) 45 with no prchistrie dicrders Renate As typotesin high skins with schizopbenia or wth SPD cidenced couialeat degre of corti sleal enlargement: oth 059 fidence igniScantlygrester lea! enlargement than did high Individuals with non-schizophrenia-specrum dsodert and 29 dso dere and owe Sndvidoal with end those without pochatrie di order (ce Figure 2) Highsisksndividaal with schisnpienia ev ‘enced signifeany greater venticlar enlargement than all he other roupe The elaped ventricleschizpbrenis Gating relate mail © pisdomiounly negative spor schizopheeia “We conc that among high-risk offspring cortical abnormalities (because of near developmental flure telat toler! of neti ik) awe caprened equally acres the schaopbrena spectrum (SPDs and tchizophrenis prim) Sobeorcal abnormales are mote. pro ounced and specific w schizophrenia. Above, we indie Oat 23 ‘anportant source ofthese subcocial abnormalities was DCs among ‘those wh hare eed the fret hit Cannon tal (1994) have ported ‘ales that there wee low lel of DCs ong SPD pavers: Discusion Individuals wih the diagnos of SED and those with the dsgrasrof| schizophrenia share the experience ofthe fst ht that rests in conta snomaliee Paints with SPD may not be schizophrenic becante they ” Sui a —_ Non Spectra Dore Ml No mest tess [errs Poy esa 455 85 8 Standardized CSF Brain Ratio tn gov io igh an lows pip Sel CSPI ato are fortunate enough to soi postpregancystesors, sac as DCs or lunsable imdies Those who have experienced the Sie bit and safer [DCs evidence widened ventricles In thi std we have only considered the genetic source ofthe fist hit In discussing Projet 2 the Fetal Vie Infection Project, we examin the interaction ofthe infiteneatertogen with Dee High-Risk Project, Hypothesis 3 ‘We hypothesis that for those wo have suffered (genetic) fist hit and have not suffered severe DCs, the rick of schizophrenia will be Increased if they ae xpoued to unstable rearing crcstances Uns 8be rearing ctcumstances wil nt increase rik for sbizphcais anon, ow isk ndvidale Background ‘We lve supported this pothesis fn the cones ofthe 1962 high-k sendy (Cannon, Mednick, & Parnas, 1950b; Wales, Cadack, Mednick, {&Schulkinge, 1981) withthe inital group of 15 schinophreia patients. We have now completed a study of fay searing and 1989 oxtcomes, with 31 sehiaophrenia pens fom the Meh group Methods From but tage 15 years, we have coded month by month, te rearing history ofthe partcipans of the 1962 High-Risk Project, indicating wheter the child war with his or her biological matter, bclgia father or both ose reared in family with no pach es or teazed in abl care nataton for normal chien Renate ‘We replated caer seul: Among high-risk participant rates of due schizophrenia ate highest forthe zeared in a plc cre isi= tution lower for those ried by a chiophreni parent. end lowest for those ried in normal foster famay (Gukind gt al, 1998) These ndings ae especialy signicant for those placed in inition before the age of 3 years All of these difrenes are statically siguicant (Goth e al, 1998) Rearing creamsance, however, do uot elit 0 Fk of schizopheni in te low-risk group PROJECT 2; FETAL VIRAL INFECTION “The Fetal Vil Infection Project focuses on theft hit ofthe working rode), she disuption of fal neural development. The Fetal Vie! Project was based on the hypothesis that teratogenic tune in fetal brain developmen dering the 2od trimester of gestation may i crease the risk for sme forme of achizophreit. 36 Barly Studies of Teratogenicity In the 1th cantry, it Became clear that exogenous chemical and py ‘cal conditions could advesely affect the embryonic development of many species. Studies were conducted, however, only on species whose ferization and development took place one the mother (chino- dams [esa rchins), amphibians nd fish) Mammaiin embryo, ‘whose fersaon and development were better protected nd tok place at an almost constant tmperatze, were bel! to be relative n= pevios 1 external chabeage Maformatios of newborn mammal wee, nevertheless observed ‘With the manmatian fetus so well protic yas though that male foxmations must be due to genetic fsre This wae the wow unl the 1930s whem Hale (1855) reported liter of 11 piglets born without yeballe The parents had orm eyes and were previowly (and sabe sequent) abe to produce ofspring with normal ees Hale raced thie deficit 0 2 dit lacking in Vitamin A daring the fated pregnancy ‘Waslany(1965)—wbo is considered by many to be the fate of mam ‘mala tretology—conducted systematic eis of suds on the ef fees of sbofavin deficiency on the slot deveoproent ofthe ft at Because the effec of ofan defiency havea gradual onset snd termination, Wakany developed » method to deterzne cial pris luring gestation of senstvity tothe exposure He administered gale toflavin. which uid acs to ibibst many actions of riboiavn. The fictfavn produced the equivalent of «riboflavin dfieny of rapid ‘niet When the galactofain was retoved, the riboflavin rpily te sumed i normal potency This methodological innovation permed Warkany to determine ith some precision the spe etl anemalies sscocited with exposure daring spec stags of gestation This ise ofthe “sharpness” (Wirkany' tem) of the methodoloicl tool sre frant to the purpose of thir reieich, An influenza epidemic has @ limited duration and therefore can bea teltely sharp methodologic tool (ative to teatoges, eg, smaking oe rata tes) In this = seare, ve were interested in laming whether « materal influenza infection during a specific portion ofthe gestational perio ie asociated ‘with adult schizophrenia (McClure, 1995) vMavernal Exposure to Infection Madnick, Machon, Hattunen, Bonnet (198) reported an seve rate of schizophrenia among Helinki residents exposed tothe 1957 inueraepiderai during tec 2nd trimester of gestation Those results forthe 1957 epidemic have bees replicated in independent scudiescom- ‘ted ia enomber of interationa settings (Adams, Kendell Hare, ‘Mank-Frgemien, 199 Fahy Joes, Shar, ak, Murray 199; Kee al & Kemp, 1965; Kanu, Tak, & Nanko, 1994; Machon & Mednick, 1994; Mednick, Machoa, Hattnen, 8 Bart, 1990; O'Callaghan, Shar “Take, Glover, & Moray 1991; Waddington, 1982; Welham, McGratb, {& Fenberton, 1993) Seed ofthe reports are specie to Month 6 of festation (Bas, Mednick, & Mank-Jorgensen, 1990; Kendell & Kemp 1965, Kanugi st al, 1994 O'Callaghan et al, 1991; Sham et aly 1982) Allo these rocesflreplations used approximately the same methodology a the original Hesnt study Thete have been fou fi {aes to teplicate these ndings Bowler & Tore, 1990; Crom, Don, 8 Jobmstone, 1991; Slien & Sle 1994: Susser, Lin, Brown, Lamey & Erlemeyer King 1998), We sould pine out that in none af tee ‘nadies was any direct evidence of ary actual matemal infection dem Malpas In Denmark, studying over 7500 schinphrenia patients we noted that ont petod of 40 yeas and acrom setie of inves epidemics, giant orem nurbers of schizoplzeaia patents vere born 4 ‘menths after periods with unduly bigh population level of aunza {infection (are etl, 1950). la other words sf her was an omasually virulent inflenea epidemic during an individual's «@&h month of se tation, that indvival bad a significantly cevated sk of adult shzo ‘ren This fading has abo bon repiatsd in fre muliepiderie Sie (Barrel, 1990; Morris eal, 199K Sham eal, 1992; Tak (cal, 1994, Welham etal, 1993) Importance of Viel Sti “The via spidemiologicl stds ae important for two reasons Fist they enpliate #neual developmental dlrrbance inthe logy ofa. least some forms of schisophrenia. Second, the delimited duration of the infuesza epidemic mas it posible wo estimate the period of ge talon ctl for schizophrenia. Viral infcous mast account for only 1 Sracton of the caves of schzophreni, genetic factors and other te opens, ofcourse, ao ply a ole. An influenza infeson ocutring at 2 etal period of near development my pertally mimic or exe ‘bute the genetic etlet Thece ase noaeplicaton, bt on the whole, however, the repiations ofthe Heldodi 1957 epidemic finding nd the euliepiems indngs suppor the hypothesis that a 2nd-rimester maternal infiuenzs infec om aces rk fr adult schiaopheents i the apr Fetal Viral Infection, Hypothesis 1 (A of the tues described shove examined only the expose of the mother tthe viral epidemic We hypothssae Ot a greater proportion ‘of mother of schiopirena patent exposed daring the 2nd timestr wll have aufered an sntentl clini documented fflenes infection than mothesof schizophrenia patients exposed in the it wimests, 3d trimester, or both Background In all ofthe carer stds, te increaed risk of infection was missed bythe overlap ofthe 2nd trimester af gestation With the height ofthe inflensa epidemic Thee iso evidence that any ofthe women actly suffered a vil infetion Te was deemed important to anchor the find. ings by demonstrating prospectively obtsned, documented evidence of sn actual infection Methods 1 ansilpation of the 1957 iflcnsn pandemic the ath authorities of Finland requested that the obstetrical mares in maternity clinics be alert to record influensa infections in pregasnt women Boose Finnish ‘women vist these matey clinics an average of 13 times during the pregnancy, the reports of the obstetrical nurses were made in dose 8‘expo! proszity to the time of the infection We checked shiao- rena patente whose 2nd trimester of gestation ocearred during the eight ofthe epidemic o determine whether thei mothers had 20 antenatal dine ord of« documented indvenz infeion Reals We found that of the Hei schizophrenia patients whose 2d wi rmerter of geaion overlapped the height af the epidemic, 667% had sm antenatal dine record ofa 2nd trimester, matemal. oper rei ‘ory infection during the 1957 pandemic Only 20% of those exposed sn the let or Sed mest had an antenatal cline reord ofa mera! infection (the population cate of infection in Henk during thee ‘demic wa 209 Machen & Mednick, 1994) Te must be recalled that | certain mumber of the 1957 bith cohort would have bncome adult ‘ehizorenia pints without the epidemic Ths, we ae bypothei: ing that the ateralinflucnza resus in an incite in number of ‘chizophrenle patients among individuals whose mothers sufered an inoeara infection inthe 2nd trimester. allows, therfore tht all of the exes of nd trimester schiaopheenia patents shoul have expec snced + maternal 2nd-trinoter Infection. This seems to be done © ‘wat we observed (Machon & Mednick 194) etal Vieal Infection, Hypothesis 2 We propose that schisphvenia paints exposed to a 2nd erimeste ‘eratogen wll evidence» pater of einical smptoms distin dt ferent fom the syiptoms of schizophrenia patients not exposed {0 fhe 2nd trimenerteratogen or who were exposed in the Ie oF 3rd Background As reported belo, we found no interaction berwoen genetic predispo- sition und he tertngen, maternal iflcnra Thi suggests that these tologi fictr ze sociated with dierent subtypes of schizophrenia ‘We examined the patients ofthe eink schizophrenia study (Madnick Sibert, 1988) to determine the 2ndtsimestrschizophania ps ‘ints evidenced disinctive pattern of symptom. The patients were interviewed and bosptl records were coded for 172 saptoms. We sabe symp ating 1 factor analysis and found ight symptom foes We compared the factor scores for each ofthese eight factors in the And-trimeter schizophrenia paints with thos of contrl rope The Ind-vimester schiophuenia patients wee significantly elevated on thse of the fics elated to paranoid tit: spciousnes delusions of elezence, nd dlsions of eslousy (achon & Made 199). Thee at appear to indlste that trtogen elt sehiophenia patents evidence 2 disorder domioatd by suspicion ay paraeid symptoms Fetal Viral Infection, Hypothests 3 For this hypothesis, we propose that Uxatgenic agents (eg 4 2nd- twimester maternal nfuenz infection) wil interact with genetic rk increne sk fr acizophcenia patients Thus, nd-aimeser materas fnfuensa should be strongly asocated with adele schizophrenia ‘patente among individuals with elevated genetic predisposition for schizophrenia Background Onty a small number of ferses exposed to maternal induenzs in the 2nd trimester actualy become schizophrenia patents Pechaps the ma- ternal lfluensa only inetease rk for adult schizophrenia in fetus aleady made vulnerable by genet predisposition Methods "To west this hypothsis, we asked whether the strength of the 2nd- telmerter effect incetce a8 « fonction of increasing genetic prdlape- siton for schizophrenia. We fist texted thie bypotbess in te contot ofa dataset, which vas onstrated by selecting all schiopbrenis po tient in Finland and then ientiing tei ret degree relatives From these ilies, we selected al those horn inthe 9 onthe aftr the 1957 fnflensa epidemic and vided hems into thee groupe on he bass ofthe ties of gestation ducing which hey wre exposed tothe epi demi. Each of thee thre trimester groups were farther divided into thre subgroups (high, medium, and low) onthe bss ofthe percentage of tei rt degree reloties who were diagnosed as ahizophrenic A ‘orparion ofthese groupe permited ws oases the strength of the in groups at varying levels of genetic isk for Renee ‘The hypothesis was not supported Ae gene rik increased om low te high) the stengh of the 2né-temeser infvensa eet decreased sienifcanty Mthodalogca! Probie ‘The index case was the family member exposed tthe 1957 epidemic Aluring gestion We arrived at degree of genetic ik fr this individual by compatag percentage offiret-dgree relives disgnoed a shi ‘hvenie Under some condidons. this terion of rick may be awed lec us tke an extreme example; consider two probands, ea with 0 fir degre relives Suppose that ia Case the wo teities ae the patents ofthe proband, wher Case 2 the two relatives ae eng ‘ofthe proband {withthe parents missing) The zens of Case 1 msy 50 years of age and wil have gone though’ = major part of thet "Hak petiod for the onset of schivaphtenia, The two siblings of Case 2, ower may be Mand 15 yeas old Clay, we mst make a deter mination of depree of familial ik that swat aed by the ae of he family merabersasesied To do this we must supplement information| fon the percentage of affected fastdegee ries with information oa the number and ages of the paris and slings of the index cue Although ve didnot have thi information for dhe tral nation ef Fa Jind, we di havea comparable ata set iia to ceria urban tes ‘of Finland that does have information on the numberof parents and siblings and thee ages Tks data set permis sto compute the geoe ie idk ofthe index case, aking into accoont the ptiod of rick expose (ages) of the fandy member, 2 (Clelating Low Risk Rates In the dit set tat includes of Fnlind, we included ony fais that contain at Ist one achinphreni pation. The index fm oem ‘ber was bor in the 9 months folowing the 1957 epidemic We defined degree of genetic rk othe indo case by the percentage ofthe other tmerabere ofthe fanay wth schinophrenin For this dats st owere, tne donot have fais in which (a) a child without schizophrenia) ‘wes bom inthe patedemic ptid and () thee ae no sehizaphreni Fatients among the other mabe of the fanily This lace group i Dvd to calulate the rte of schizophrenia among index ces ho ave mo first-degree reéatives with schizophrenia low-ik group) “Above we ave described an urban Fina. population that iden tie al Finns born in thee affected eran areas ater the 1957 American Pyhite Amacition (1987) Ding an titi! mona of etl dds (ed ev) Wshinpon, DC: Astor American Poche Auction (1994) Dag and ial mana of ‘metal donde (Ah e8) Washington. DC: Autor ‘Andesen, NC (1988) The Sale forthe Asomet of Negative Symptoms {SANS Towa Ci Unies af ows Andresen, NC (1585) The Sale fr the Asem of ie Sopot (SAPS) toma Gay: Uses of fv. Barer, DP (1998) Mats haber and tei er fe London: Bish Mei Journal Bars By Mech S A. 8 Munk-forgemen, (199) Expose tonne ‘iden during pesto a sd echinnghrenie A -jear eady Ar ‘hes of General Pay, 969-14 ‘Ben Ass Y (1952) fees of anos and agent of the dal nd atre ppocpes Silay of th Nerats 62, 225-290 Bowles, Tose E (1990) laura and sehisop hres Hind ad Eliburgh Arh of General Phin 47, 616-877 rf D1, Sarwan D P1985) Thetine couse of oration prceing ei in eizptenia Amerie Jura of Pein, 142,170 aBena, A W (1985) Fc during sonal ita ines ran done Tn D Fen (8), Presa end prt ao ace wt ra ries (gp 253-338) Wahngon, DC Nationals f Hest cannon, TD, Fatman, M, Mednic 5A, Mickon, A, Par 8 ‘Sthaings F (986) Thi vente eargament and reduced deso- onmalerponsnenes Pyehoppila 25 153-156 cannon TD. 8 Madi § A (1989) Gone a prin dermis of wu an dts in eaopens Artie of Gel Pyar, ‘Cansom,¥ Dy Mednick § A, Be Parah 1 (8506) Atendent of ped Tnuatysepive- end pedominany pose spt hiss a 1 high-k popltion Archie of Genera Pci 7, 22-652 Cannon TD, Medic § A 8 ares, F (9908) Two pty ohn irra iden t Ze In L Robins 8 M. Rater (as) Semi at leon potas fro Chhaed 9 adulthod (pp 325-350) Combi, Brglind Cambridge Unies Press Canaan ¥ B, Mec, § Feo. Schaige , Peele 1, Se ‘Vespa (0999) Deepen rain borates ete ofr oF schaptreie mothers | Conrbtione of pnaic and peri fe. ton Archies of Gone Prchiy $0 551-S6h, cannon, TB, Madnick 5 Ay Perm J, Suing F, Prva, 8 Ven (19%) Developmental ban abnormal inte otigeing of shiopbvenie mith Il Seuctin ban carci of wine henna actiaoepl peony order Archi of Genel yea 9,51, 985-862. Com 1, Done.D 1. Srshntone © (191) Sabicea ndinueaea ane 338, 118-117 Endicott, & Spits R (972) Gument and Past Paychopthlogy Sales (CARES) Archies of Gone Pyehing 27. 68-647 Ty A, Jon FB, Sb PC, ake Neer. M (193) Seino ‘pie in Ao Carbeas in the UK ooring rental expose 1 the 1857 A infin peri Sckopveia Rexarch, 6 98-99 Gor, (987) Venache mit eter an Dre [Resnech et be ‘row Reye Suse Zong 3, 67712 Catkind D, Mednisk, B. Canon, T, Para, Scuboge F & Mednick, @ ‘S.A (199) Parental eh ond sepia —A 27. yar fol of ‘he Coperbger highs chore Manus seed for pletion Mle, F 0938) is bor wou ep ale fara of Hee 26, 105-106 osise,)M, Laing , Ae Modnick 5 4 (1996) Res inom at id facto chip ole nts Ach of Gar Pic fry ss. 19-24 oti, M, Mednick § A. Brennan, Cannon, T B (198) Inpaied tonomic neous ser abr in hot get ik fo chi nin Archies of Genel Pca, 5, 82-558 Mein, MO, 4 Nisan, (1973) renal lou fier end pci aoners Archins of Gel Phi 528-481 Jose, V, Loh JB (188) Hippocampal pole Sng in ahio- ‘prea Archives of Genel Pei 46, 119-1024 Kanon, © N, Gascn Ril, Beidrmann, 7A, Mink, Mula, MM, 1 Skinne, ED (191) The bran sem elt frsation in vebiae- nin Phony Rear 40 31-46 endl Ey & Kemp. 1 W (1989) Mate iene in the elegy of sxhinoplveala Are of Generel Pohiay 45,#78- #82 aong Hy TN, & Naaks, § (1994) Hed camber a bik and ‘ehaopueia Beh oar of Pach 16, 274-273, ang P. Right 1G, Wight Pe evng, W 1 (1995) Dien ofl ‘ain development iy mitra snbodi 2 nl aor in = ophrein Jo $A Mednick TM Halse (Be), Nel neler fn shiscproi Theory and nach (pp 215-246) New York Pana Vonage AW, Susman, VL, Oldham, | M. & Ros LM. (985) ‘Feronalt Diner Bena 8 acre ater for ing a ro of DSM peat ddan White Pans NY Cael Mabel Gage Macon, R A, Ke Mani, § A (994) Ada chip od ey - ‘odevdlopnental diturbances In A Zamacla. 1 Ribera &B Ha ‘un-Gowl (8), Conforteons pehaiges Epon phi tie hire confrontation and echiy) ( 33. 99 199-215) Pa France Spec Rhone Polen Rover Macon R.A, Malas A, Maruman MO (1997) Adena ie 6oder floing penta exposure to a noes pide Arkin ef Genel Paha 8432-328 Declare, W 0 (195) Fetal deveopment and sinopheia: Hora ob ern Go taalgy In § A Mack &) M Moline (Bi), Ne tal depen icp: Thy and rach (pp 18-26) New ek Plena Pe Mena, TF (1968) Ober aos and pera res Ea MT Teg 1) © Sinpon (Ea) Hendbeok of sckcphrei pp 319-348) Amo sear: Eee Mahi § A (199) Breakdown i indivi thigh rior -soprene ost pedaporioal part ste Akt Hypien, 50-63 Medak $ A, Macon RA, Hattunen, MO, Bure B (1990) Inloen| tod sczopren: Hein vs Blnburgh Archi of General eh 1, 095-896 Meinik § A, Machon RA. Hotunen: MO, 8 Bonnet D (1955) Adal schizophrenia lowing penta exporue fo an infer epidemic A dav of Genre Phin 5, 189-192 Mednick § A, 8 Seton L 1988) High sdes of te elegy of Scuopvena In MT Thuan & © simpson (Bs) Hans of ch pivots Gd 3: Newly eptemislgy end genic (9 $4552) Am ‘Sonn: Hate Stee Modi Mf, Cote, D, Take N, Walt, D. Larkin ©. Wingo, “OCalghn,E (950), An aciaton been schiophanc Binh nd Inerea gents in edad in he yeas 1921-1971 Schssprenia a> rch 9,7 ‘Ocataphan,£, Sham Ps Tab N, Glow, Gy & My R (191) Sbio- phen afr pret epost 1957 AZ Inguena epidemic Laver 37 1208-128 Panay, Canon. T D,cbten B, Shang, Scubinge F 6 Me ick § A (993) Lifeine DSMGITLR éagnaic outcome in the of ‘nig of schizo mothers eral Rom he Copeiagen igh sk stl Aries of Gena Pci, 50, 77-74 Peten NS, Mich HK (1882) Eas of Ret shock on gene et ‘reson during dewlopent Enduston and prevetion of the ule enocopy SM J Schlager M Adbrer, A Tisres (Bs) Hest os sh fom bactrim 35-52) Cad Spring Harbor ME: Cel Spring Hubor Laboratory ik, 7, Geepion, A, Adolph M, & Lbowte, $ (981) Tae bebsvor ‘of ena nd mare is xpd eet a-aeantode ins Jura of Neng 3-419 Senger MJ, Asura, MB Tiere, A (1982) Hat sack fom be tit» man ald Spring Harbor, ME: Cod peng Harkor Laboratory Seen, PSF. (1998) idence pit mate inflonea ‘cof ehignpheni Brith Jol of hi 16% 674-676 stam, F.C, Otalughan, ETN, Mary. Kare Efe Mora R TM. (1992) Sskinoprenia wing pre-and enone 0 infaeast ‘piensa 139 and 560th Jara of Pca, 260 Site. A (1895) Evie difecencs ip any and te 1 Jounal of Cid Pyehoy ont yeh, 34, 09-12 Spl, K Ly niet, J (1977) Schedule Jor Afeine Dron a ‘Schrpvenia-Liftine eset (de). New Yr ene York Ste Boy ‘bite use Suey Lin, Brown A S, Lames LH & ElenneyerKinking L (Qo!) No saon tooern rk of hbpbreis sd precatal epost to ines in olan American oral of Pct, 151, 922-928 “ka, Stam, OCaagas,E, Maray G KE, Glover G8 Mewar TR M (1994) Penh expe wo Ioerss and the dowlopment of schzaphneni: le he ac conned 2 fei? Ameria oul of = hon 51, 17-09 ‘ens (1997) Mater exposre niente cldn pregnancy and lerdal aye ofpring: The Martie Sadr Pychpheg 7-035 Wadiiston, 1 (199, Jane) Schcophrni ofthe 1957 fz pion in rand. Paper rented the mig he Roya Soc of P= chiar, Dali, tend Wilkes EE, Cader, Ry Madnick A, & Shins, F (1981) The er of parent ebenue and estintionlctin onthe deve of inka symptos in Digheik cen Area Pyke Scan 8, 98‘Washay J (1968) Denlopncat of expinentl cumin tesa Ta 1.6 Wibon 8 Wacky (Ed), Tal: Prin nd sigs op 2m) Chap Une of Chicago Pe Wl.) Ly Gra}, 8 Rembern M (1993) Siar: ith ‘aerate Anatln epider Sepia Rend 42 Wing] K, Coops) BB Sarria N (1970) The merit ad lt ‘sate of Phare oye Cambri, Egat Canis Uni Genetic and Perinatal Influences in the Etiology of Schizophrenia: A Neurodevelopmental Model Tyrone D. Cannon, ns Keaepela (1918) ong Formulation, ezophieni was viewed 151 deteriorating brain dzeae, similar i natural history to Alzie- seri dbase but with onsets etsly adult fe. Despite enka obser ‘tion that cognitive deterioration ws not prec in every cas (Bled les 1911/1950), the Kraeplintn analogy 10 dementing dsnder har persed in the conslonmnett of clinicians and revarchere for mich ofthis century Ip fc when the fre studies examining the brine of {ving patients using computed tomography fest appeared in 1976, he ‘viens of gros enlarge ofthe cerebral ventricle in thee patente ‘wae nterpeted as an anatomical sigmatore” ofa dementing proces in The schisophzenicpoydoses Johnstone, Crow, rth Husband, &Kred, 1976; Jostone eta 1978) Ta dhe pat decade, hi vw has ben eadicallyalere by advances along sveral lines of inquiry tat point toa penwal-perinata ig a least sore ofthe brs abuorraities in schizophrenia Fist, merous prospective studies have found asuocatons between penal and perinval complicaions (¢@, fetal hypaia [oxygen deprivation) snd a increased rik for schizophrenia later in Iie, indiaing that obstetric evens expected to have an adverse impact on the developing @Neural Mechanisms Underlying Hallucinations in Schizophrenia: The Role of Abnormal Fronto-Temporal Interactions Emily Stern and David Silbersweig “Loiscnonanes promis netting rs ron fof schirophrens They usually tke the fora of voices talking to for about the patient, ofen in a derogatory fusion With incensed ‘eveity of ies, other modal, ach a ritual and tac, may be invoked Up to 75% of patients experience such involuntary percepts in the abence of external simul t some point in thee aes (Wing Gooper, & Suttons, 1974) A sting fature of RaBacinatons in schizophrenia in contrast to those accompanying structural neerolog ie disorders i that they often ave affective, concep, and behav ioral relevance for the patient Patents becom emotionally involved ‘with thei Paucnations, iconporate them int dlsional bb sx tems, and may even act on them ‘Given the predomimatty auditory linguist form of shizophvenic tatucnations, se wel a the lou of rat testing asta wih them, superior tepora and prefrontal abeocmaes might be postulted ‘When cosiring the tle that such neuroanatomical ees might play oe mst consider not only the information processing characteristics of iadvial subregions but alo thx patern of afeent (incoming) td efferent (otgping) conection This ls consistent with the wend 235In behavior) neuroscience over the pas decade of emphasing the ‘iacted (other than pure lcaiaed) ature ofthe neural substrates ‘of behavior (Mesulam, 1990) More recent, the neuropsrchoogial and neaophysclogiel importance of interactions among the repione ‘making up thse paral disiboted stems har alco been reengized| (itn, Fr, Fletche, Lid, & Frackowia, 1996) ‘Rapidly aévancng fctonal neuroimaging technologies when combined with arf study design provide « means ofloczing nd sGuractrisng neuronal activity associated with hurpan mental sates Postion emission tomography (PET) i « pacicularlywel- developed method of wtcstng sstemlevel activity The wie of water (FO) o© ‘arbon dioxide (CO). radiolabeled with = shore hal-ife isotope of ‘oxygen (0), lowe muti, repeated camping of rn-restl at ina single study sesion ‘These PET raioracer techniques work by meaning the regional cerebral blood fw changes coupled to loc synaptic activty With high sensi 3.dimensionlseanning peise payholopcal or psyhitie activation paradigms and appropriate a= ‘arate and maltvarnte image analysis techniques, tatty signi ant rests canbe obtained with single subject wih groups (Ere owiak & Fiston, 198) ‘We and out collegucs have performed a series of PET sais f= casing on the problem of auciaatins in shiopheenia These rds ‘we new °O activation methodologies that extend previous ingle yho- ton emision computed tomngraph and PET approaches (eviews cic ‘har, ee Slersieig & Stern, 196) to this problem, Hee, we discuss ‘ur studies in the context of Sronto-temporalinfersctions and their limplestions for symptom formation The sulle converge onthe py: chopathophysologial sues, stating witha consideration of shin ‘hreninas an overall diagnos sndome, progressing wan assesment of tat charceritie that pedixpoce to lication in schizaphe ia, and ending with an arlyis ofthe specific hallucinating atte in schizophrenia The syndrome and ait studies we a top-down ‘pprosch—sterting with some of the newropechololel prosett ‘hooght to be dsupted caning normal subjcs and patients dui, approptintely Jelgned activation and coal take that leat tote 236 processes, and contrasting the brain images avocited with Yoosetaks to loale smptomaszally relevant disiacations im brain activity Tn Contrast, the sate stad uae «Dotton-up approsch— directly mapping the neural substrates of the syaptom and interpreting the rests in light of behavioral eurscenifc principles These investigational strat egies are compemeotary and may inform one another (Siberowig ‘Str, 1996) The design and pctnent esas ofeach ty are outlined ‘eb llowed bya discon of the pathophysalogial implicsions of abnormal activity i and intrsesons berweea fron ed temporal regions PET STUDIES Words are general by patients with shizophrenia daring auitory- vesbal hallucinations, even if the patients atetbute them to anor fource Word generation thetelore iwlves a set of neuropsyhologied functions of eelevance tthe linguistic ampect of typical whizoprenic Illinios Fighten croni, medicated paint with shizophrenia {Givided ito Utee groups of six on the bass of verbal Buency pet ormance) ands age sex, premorbid IQ-mutched normal contelsub- jects wee stoded with a paced word generation, PET action pars igm (Frith eal 1995) The actraion tek involved generating words farting wth a given loner One ltr wus prevented surly evry 5 ¢ [A given leter was repeated 10 times unless the individual failed to teneate an appropise word, in which cate «new ewer was presente ‘The sensory-motor conte! task involved the presentation ofthe some ‘ype ofstzal but dhe subject was instructed to retely epet the ter aloud (hereby controlling for auditory input and speech outpat) m= ses from each condition were proceed and analyed (contrasted) ‘vith sail paramsteic mapping (SPM) techniques In he word-generation condion vrs the conta endo, noc smal sbjet activated a ditribated cortal-subcortcl stem inciud- ing the let dorsolateral pefiontal cortex, anterior cingulate, and hal ‘amas Ares of edativly decreased sctivity fo his comparison included ‘the superior tempera cortices (Lf rete than right) Paints wits awschizophrsnia, regardless of tsk performance, were able to acne the font reglons Hower these patient didnot show deceased activity inthe superior (and, to leer extent, dle) temporal cortices In fac, with a canonical varias analysis (capable of inning diteb- ted paren of nearl acviry accounting forthe experimentally n= duced varianes), the patents showed increase activity in thes tem poral regions stead of examining the overall syadome of schizophrenia, the neat study focused on the symptom teit—the predisposition to bal- Tncnate The seuropsychalogial tks wed inthis study probed the proceses of taner spech and auditory-verbl imagery Govet spect as been impieatod in schizophrenic hallucinations giver the possble dirupion of not! lingssie thought process and the variable nd lng of subwoal speech (detected with test miciophones) in sme hallucinating patients that matched the reporied concent of thet “-wice” (Gould, 199) Autory-serbal mental imagery is another in portant presto consider Like hallucinaions, imagery pret p= eotion in the absence of ermal simu Sut url hallucinacons (hich ae ivolunrary), itis under voluntary cote Three loup of sx subjocs cach were sted in this experiment —poviens ih schaophena and a isory of hallucinations (alt por ‘ve But not curren haocinating, patients with schiaophrenia and ‘history of halcinations (wait nega, patient contol), and mor sal contos (McGuire tal, 1995; MeGule Sdberoweg, Wright, eal, 1996) All groups were matched for age and premorbid IQ. Patents ‘wee alo matched for less duration and neuroleptic doe (in cor promazine equivalents) Three ass were performed in 2 eountebal snced order (o counteract time and order effects) The contrast of Task 2 vers Ts 1 eoated inner (een) speech, whereas the contrast of| “sk 3 versus Tsk 2 olted audtory-eba imagery Tn this cxperiment, there was no ference in the Function neu reanatomy of ine sete (including Broc's arc) betwen the eho ‘Phreni pints with «predisposition to hallucinate and the contol (roupe There was, however, difference in the audio verbal inagery condition Whcess noemal and putat convo showed increased 2c 238 tity in itera rostel supplementary motor cortex (in the superior radial font lobe) and left middle tmporal gyrat, schizophrenia po tients witha ballucinaton trait ectaly showed decreased activity tn these regions “o map the neu substates of aucnasons in «dct oto up fubion, we developed and validated new techniques of PET image ac- quisition and anal (Slhereves tal, 1995, 1994). The nce ten ivy and tempor discinimtion of these method allowed the stdy of sch eansent, randomly occurring spmptoms in ata manner ive points with schizopbens and casi autory-vebal alisnatons spe mediation and one day naive pte with oth vial and a - ‘mated T wonder, Boweves, what has been lead about sclzo- pinenia Consider, for example tht several investigators inceasingy report findings tat ae not specif to schizophrela, and, if anything, the carmlative daa ln greater and greater credence t the “gone v rnerbity” model of peychosis (Zubin & Spring. 1977) Mednich et (Oper 2, this volume) have found that many of the obstetric and Tort factors, in prticalan 2nd-trimerter export to inloenza virus criginaly though to be specific antecedents of schizophrenia, ae s- sociated with avery broad range of disordered behavior (eg affective sorders,amsocl behavior and implred cognition) Simla, Caes- Date al (chapter 13 ths volume} propose that he well documented attensonal defi associated with schizephrenia may have ide to do withthe eine presemation of the dsoeder In shor it spears that what researchers hae lemed tends parndonclly to be nertowy ci cumscctbed in behavioeal tems yet besdly aplcsle to pryho pubelogy TECHNOLOGY AND THE STUDY ‘OF SCHIZOPHRENIA [A move scious problem in the study ofthe schivpbsenie i ann ‘elueal hance on the tlt of technolory forthe direction of esearch and on extreme redactions as primary epistemological model By ‘exreme rduconion, | mea the sramption thet certain dorins of ceplamation, such asthe biochemical “andere” and therefore have epistemological dominance over other domaine of explanation, such st the behavioral I refer you to Miller’ article (1996) regarding the logical fallices in tempting to expan all behvira (or psychological) poe- nomena with aelecalar bislgial site The spiro thi argement io orl captured by the incon he makes between the understand Ing of time andthe understanding of how clock works Tasris about time do not require an understanding of ho the gets ofa clock werk to move the hands eround it face Clocks and ime intersot they ae sot the same, Simla, one can understand the natore of sbnormal 185